Down syndrome (Down's Syndrome in British English[1]) is a genetic disorder caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British doctor who first described it in 1866. The condition is characterized by a combination of major and minor differences in body structure. Often Down syndrome is associated with some impairment of cognitive ability and physical growth as well as facial appearance. Down syndrome is usually identified at birth.

Individuals with Down syndrome can have a lower than average cognitive ability, often ranging from mild to moderate mental retardation. Developmental disabilities often manifest as a tendency toward concrete thinking or naïveté. A small number have severe to profound mental retardation. The incidence of Down syndrome is estimated at 1 per 800 to 1 per 1,000 births.

Many of the common physical features of Down syndrome also appear in people with a standard set of chromosomes. They include a single transverse palmar crease (a single instead of a double crease across one or both palms), an almond shape to the eyes caused by an epicanthic fold of the eyelid, shorter limbs, poor muscle tone, and protruding tongue. Health concerns for individuals with Down syndrome include a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive sleep apnea, and thyroid dysfunctions.

Early childhood intervention, screening for common problems, medical treatment where indicated, a conducive family environment, and vocational training can improve the overall development of children with Down syndrome. Although some of the physical genetic limitations of Down syndrome cannot be overcome, education and proper care will improve quality of life.[2]

Contents

Characteristics

Individuals with Down syndrome may have some or all of the following physical characteristics: oblique eye fissures with epicanthic skin folds on the inner corner of the eyes, muscle hypotonia (poor muscle tone), a flat nasal bridge, a single palmar fold (also known as a simian crease), a protruding tongue (due to small oral cavity, and an enlarged tongue near the tonsils), a short neck, white spots on the iris known as Brushfield spots,[3] excessive flexibility in joints, congenital heart defects, excessive space between large toe and second toe, a single flexion furrow of the fifth finger, and a higher number of ulnar loop dermatoglyphs. Most individuals with Down syndrome have mental retardation in the mild (IQ 50–70) to moderate (IQ 35–50) range,[4] with scores of children having Mosaic Down syndrome (explained below) typically 10–30 points higher.[5] In addition, individuals with Down syndrome can have serious abnormalities affecting any body system.

Genetics

Karyotype for trisomy Down syndrome. Notice the three copies of chromosome 21

Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or part (such as due to translocations). The effects of the extra copy vary greatly among individuals, depending on the extent of the extra copy, genetic background, environmental factors, and random chance. Down syndrome occurs in all human populations, and analogous effects have been found in other species such as chimpanzees[6] and mice. Recently, researchers have created transgenic mice with most of human chromosome 21 (in addition to the normal mouse chromosomes).[7] The extra chromosomal material can come about in several distinct ways. A normal human karyotype is designated as 46,XX or 46,XY, indicating 46 chromosomes with an XX arrangement for females and 46 chromosomes with an XY arrangement for males.[8]

Trisomy 21

Trisomy 21 (47,XX,+21) is caused by a meioticnondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 21; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo now has 47 chromosomes, with three copies of chromosome 21. Trisomy 21 is the cause of approximately 95% of observed Down syndromes, with 88% coming from nondisjunction in the maternal gamete and 8% coming from nondisjunction in the paternal gamete.[9]

Mosaicism

Trisomy 21 is caused prior to conception, and all cells in the body are affected. However, when some of the cells in the body are normal and other cells have trisomy 21, it is called Mosaic Down syndrome (46,XX/47,XX,+21).[10] This can occur in one of two ways: A nondisjunction event during an early cell division in a normal embryo leads to a fraction of the cells with trisomy 21; or a Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert back to the normal chromosomal arrangement. There is considerable variability in the fraction of trisomy 21, both as a whole and among tissues. This is the cause of 1–2% of the observed Down syndromes.[9]

Robertsonian translocation

The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation. In this case, the long arm of chromosome 21 is attached to another chromosome, often chromosome 14 (45,XX, t(14;21q)) or itself (called an isochromosome, 45,XX, t(21q;21q)). Normal disjunctions leading to gametes have a significant chance of creating a gamete with an extra chromosome 21. Translocation Down syndrome is often referred to as familial Down syndrome. It is the cause of 2-3% of observed cases of Down syndrome.[9] It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.

Duplication of a portion of chromosome 21

Rarely, a region of chromosome 21 will undergo a duplication event. This will lead to extra copies of some, but not all, of the genes on chromosome 21 (46,XX, dup(21q)).[11] If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics. This cause is very rare and no rate estimates are available.

Incidence

The incidence of Down syndrome is estimated at 1 per 800 to 1 per 1000 births.[13] In 2006, the Center for Disease Control estimated the rate as 1 per 733 live births in the United States (5429 new cases per year).[14] Approximately 95% of these are trisomy 21. Down syndrome occurs in all ethnic groups and among all economic classes.

Maternal age influences the risk of conceiving a baby with Down syndrome. At maternal age 20 to 24, the risk is 1/1490; at age 40 the risk is 1/60, and at age 49 the risk is 1/11.[12] Although the risk increases with maternal age, 80% of children with Down syndrome are born to women under the age of 35,[15] reflecting the overall fertility of that age group. Other than maternal age, no other risk factors are known. There does not appear to be a paternal age effect.

Prenatal screening

Pregnant women can be screened for various complications in their pregnancy. Many standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical blood sampling (PUBS) are usually offered to families who may have an increased chance of having a child with Down syndrome, or where normal prenatal exams indicate possible problems. Genetic screens are often performed on pregnant women older than 30 or 35.

Amniocentesis and CVS are considered invasive procedures, in that they involve inserting instruments into the uterus, and therefore carry a small risk of causing fetal injury or miscarriage. There are several common non-invasive screens that can indicate a fetus with Down syndrome. These are normally performed in the late first trimester or early second trimester. Due to the nature of screens, each has a significant chance of a false positive, suggesting a fetus with Down syndrome when, in fact, the fetus does not have this genetic abnormality. Screen positives must be verified before a Down syndrome diagnosis is made. Common screening procedures for Down syndrome are given in Table 1.

Uses ultrasound to measure Nuchal Translucency in addition to the freeBeta hCG and PAPPA (pregnancy-associate plasma protein A, OMIM176385). NIH has confirmed that this first trimester test is more accurate than second trimester screening methods.[18]

Even with the best non-invasive screens, the detection rate is 90%–95% and the rate of false positive is 2%–5%. False positives can be caused by undetected multiple fetuses (very rare with the ultrasound tests), incorrect date of pregnancy, or normal variation in the proteins.

Confirmation of screen positive is normally accomplished with amniocentesis. This is an invasive procedure and involves taking amniotic fluid from the mother and identifying fetal cells. The lab work can take several weeks but will detect over 99.8% of all numerical chromosomal problems with a very low false positive rate. [19]

Due to the low incidence of Down syndrome, a vast majority of early screen positives are false.[20] Since false positives typically prompt an amniocentesis to confirm the result, and the amniocentesis carries a small risk of inducing miscarriage, there is a slight risk of miscarrying a healthy fetus. (The added miscarriage risk from an amniocentesis is traditionally quoted as 0.5%, but recent studies suggest that it may be considerably smaller (0.06% with a 95% CI of 0 to 0.5%).[21])

A 2002 literature review of elective abortion rates found that 91–93% of pregnancies with a diagnosis of Down syndrome were terminated.[22] Physicians and ethicists are concerned about the ethical ramifications,[23] with some commentators calling it "eugenics by abortion".[24] Many members of the disability rights movement "believe that public support for prenatal diagnosis and abortion based on disability contravenes the movement's basic philosophy and goals."[25]

Cognitive development

Cognitive development in children with Down syndrome is quite variable. It is not possible at birth to predict their capabilities, nor are the number or appearance of physical features predictive of future ability. The identification of the best methods of teaching each particular child ideally begins soon after birth through early intervention programs.[26] Since children with Down syndrome have a wide range of abilities, success at school can vary greatly, which stresses the importance of evaluating children individually. The cognitive problems that are found among children with Down syndrome can also be found among typical children. Therefore, parents can use general programs that are offered through the schools or other means.

Language skills show a difference between understanding speech and expressing speech. It is common for children with Down syndrome to need speech therapy to help with expressive language.[27]Fine motor skills are delayed[28] and often lag behind gross motor skills and can interfere with cognitive development. Occupational therapy can address these issues.[29]

In education, mainstreaming of children with Down syndrome is becoming less controversial in many countries. For example, there is a presumption of mainstream in many parts of the UK. Mainstreaming is the process whereby students of differing abilities are placed in classes with their chronological peers. Children with Down syndrome may not age emotionally/socially and intellectually at the same rates as children without Down syndrome, so over time the intellectual and emotional gap between children with and without Down syndrome may widen. Complex thinking as required in sciences but also in history, the arts, and other subjects can often be beyond the abilities of some, or achieved much later than in other children. Therefore, children with Down syndrome may benefit from mainstreaming provided that some adjustments are made to the curriculum.[30]

Some European countries such as Germany and Denmark advise a two-teacher system, whereby the second teacher takes over a group of children with disabilities within the class. A popular alternative is cooperation between special schools and mainstream schools. In cooperation, the core subjects are taught in separate classes, which neither slows down the typical students nor neglects the students with disabilities. Social activities, outings, and many sports and arts activities are performed together, as are all breaks and meals.[31]

Health

The medical consequences of the extra genetic material in Down syndrome are highly variable and may affect the function of any organ system or bodily process. The health aspects of Down syndrome encompass anticipating and preventing effects of the condition, recognizing complications of the disorder, managing individual symptoms, and assisting the individual and his/her family in coping and thriving with any related disability or illnesses.[32]

The most common manifestations of Down syndrome are the characteristic facial features, cognitive impairment, congenital heart disease, hearing deficits, short stature, thyroid disorders, and Alzheimer's disease. Other less common serious illnesses include leukemia, immune deficiencies, and epilepsy. However, health benefits of Down syndrome include greatly reduced incidence of many common malignancies except leukemia and testicular cancer[33] - although it is, as yet, unclear whether the reduced incidence of various fatal cancers among people with Down syndrome is as a direct result of tumor-suppressor genes on chromosome 21, because of reduced exposure to environmental factors that contribute to cancer risk, or some other as-yet unspecified factor. Down syndrome can result from several different genetic mechanisms. This results in a wide variability in individual symptoms due to complex gene and environment interactions. Prior to birth, it is not possible to predict the symptoms that an individual with Down syndrome will develop. Some problems are present at birth, such as certain heart malformations. Others become apparent over time, such as epilepsy.

These factors can contribute to a significantly shorter lifespan for people with Down syndrome. One study, carried out in the United States in 2002, showed an average lifespan of 49 years, with considerable variations between different ethnic and socio-economic groups.[34]

Fertility amongst both males and females is reduced,[35] with only three recorded instances of males with Down syndrome fathering children.[36][37]

Genetic research

Down syndrome disorders are based on having too many copies of the genes located on chromosome 21. In general, this leads to an overexpression of the genes.[38][39] Understanding the genes involved may help to target medical treatment to individuals with Down syndrome. It is estimated that chromosome 21 contains 200 to 250 genes.[40] Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome,[41] located proximal to 21q22.3. The search for major genes involved in Down syndrome characteristics is normally in the region 21q21–21q22.3.

Recent use of transgenicmice to study specific genes in the Down syndrome critical region has yielded some results. APP[42] is an Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties.[43] Another gene, ETS2[44] is Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."[45]

Sociological and cultural aspects

Advocates for people with Down syndrome point to various factors, such as special education and parental support groups, that make life easier for parents. There are also strides being made in education, housing, and social settings to create environments which are accessible and supportive to people with Down syndrome. In most developed countries, since the early twentieth century many people with Down syndrome were housed in institutions or colonies and excluded from society. However, since the early 1960s parents and their organisations (such as MENCAP ), educators and other professionals have generally advocated a policy of inclusion,[46] bringing people with any form of mental or physical disability into general society as much as possible. In many countries, people with Down syndrome are educated in the normal school system; there are increasingly higher-quality opportunities to mix special education with regular education settings.

Despite this change, reduced abilities of people with Down syndrome can pose a challenge to parents and families. Although living with family is preferable to institutionalization for most people, people with Down syndrome often encounter patronizing attitudes and discrimination in the wider community. In the past decade, many[How to reference and link to summary or text] couples with Down syndrome have married and started families, overcoming stereotypes associated with this condition.[How to reference and link to summary or text] [this contradicts earlier statement regarding fertility of just 3 recorded cases of men with Down's syndrome becoming fathers]

The first World Down Syndrome Day was held on 21 March2006. The day and month were chosen to correspond with 21 and trisomy respectively. It was proclaimed by Down Syndrome International.[47] In the United States, the National Down Syndrome Society observes Down Syndrome Month every October as "a forum for dispelling stereotypes, providing accurate information, and raising awareness of the potential of individuals with Down syndrome."[48] In South Africa, Down Syndrome Awareness Day is held every October 20.[49]

History

English physician John Langdon Down first characterized Down syndrome as a distinct form of mental retardation in 1862, and in a more widely published report in 1866 entitled "Observations on an ethnic classification of idiots".[50] Due to his perception that children with Down syndrome shared physical facial similarities (epicanthal folds) with those of Blumenbach's Mongolian race, Down used terms such as mongolism and Mongolian idiocy.[51]Idiocy was a medical term used at that time to refer to a severe degree of intellectual impairment. Down wrote that mongolism represented "retrogression," the appearance of Mongoloid traits in the children of allegedly more advanced Caucasian parents.

By the 20th century, "Mongolian idiocy" had become the most recognizable form of mental retardation. Most individuals with Down syndrome were institutionalized, few of the associated medical problems were treated, and most died in infancy or early adult life. With the rise of the eugenics movement, 33 of the (then) 48 U.S. states and several countries began programs of involuntary sterilization of individuals with Down syndrome and comparable degrees of disability. The ultimate expression of this type of public policy was the Germaneuthanasia program "Aktion T-4", begun in 1940. Court challenges and public revulsion led to discontinuation or repeal of such programs during the decades after World War II.

Until the middle of the 20th century, the cause of Down syndrome remained unknown. However, the presence in all races, the association with older maternal age, and the rarity of recurrence had been noticed. Standard medical texts assumed it was caused by a combination of inheritable factors which had not been identified. Other theories focused on injuries sustained during birth.[52]

With the discovery of karyotype techniques in the 1950s, it became possible to identify abnormalities of chromosomal number or shape. In 1959, Professor Jérôme Lejeune discovered that Down syndrome resulted from an extra chromosome.[53] The extra chromosome was subsequently labeled as the 21st, and the condition as trisomy21.

In 1961, nineteen geneticists wrote to the editor of The Lancet suggesting that Mongolian idiocy had "misleading connotations," had become "an embarrassing term," and should be changed.[54]The Lancet supported Down's Syndrome. The World Health Organization (WHO) officially dropped references to mongolism in 1965 after a request by the Mongolian delegate.[55]

In 1975, the United States National Institutes of Health convened a conference to standardize the nomenclature of malformations. They recommended eliminating the possessive form: "The possessive use of an eponym should be discontinued, since the author neither had nor owned the disorder."[56] Although both the possessive and non-possessive forms are used in the general population, Down syndrome is the accepted term among professionals in the USA, Canada and other countries; Down's syndrome is still used in the United Kingdom and other areas.[57]

↑ 16.016.1For a current estimate of rates, see Benn, PA, J Ying, T Beazoglou, JFX Egan. Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustments for cross-identification and double-positive results. Prenatal Diagnosis21 (1): 46-51.PMID 11180240

↑Assume the false positive rate is 2% (at the low end), the incidence of Down syndrome is 1/500 (on the high side) with 95% detection, and there is no ascertainment bias. Out of 100,000 screens, 200 will have Down syndrome, and the screen will detect 190 of them. From the 99,800 normal pregnancies, 1996 will be given a positive result. So, among the 2,186 positive test results, 91% will be false positives and 9% will be true positives.

↑A planning meeting was held on 20 March1974, resulting in a letter to The Lancet. (1974). Classification and nomenclature of malformation (Discussion). The Lancet303 (7861): 798. The conference was held 10 February-11 February1975, and reported to The Lancet shortly afterward. (1975). Classification and nomenclature of morphological defects (Discussion). The Lancet305 (7905): 513.